This invention relates to a pharmaceutical composition comprising a water-insoluble medicinally active substance, surfactant(s) and solid carrier(s), which has very satisfactory dissolution property, oral absorbability and so on. The pharmaceutical composition of the present invention can be used in the field of medical care.
To provide a pharmaceutical preparation of a water-insoluble medicinally active substance, particularly a pharmaceutical composition for oral administration, it is common practice to cause a polymer such as hydroxypropylmethylcellulose and the medicinally active substance to form a solid dispersion, and typically such a solid dispersion has been proposed for the under-mentioned FK506 (or FR-900506) which is well known to have a potent immunosuppressive activity but be insoluble in water (Japanese Tokkyo Kokai Koho S62-277321). 
However, it is generally acknowledged that the absorption of such a solid dispersion after oral administration has a tendency toward some variation. The inventors of this invention did intensive research and have succeeded in developing a pharmaceutical composition which, even in cases where the active ingredient is a substance which is insoluble in water (i.e. a water-insoluble medicinally active substance), assures very satisfactory characteristics such as favorable dissolution property, high absorption, and/or less variation in said absorption.
This invention is essentially directed to a pharmaceutical composition comprising a water-insoluble medicinally active substance, surfactant (s) and solid carrier(s) and to a process for producing said composition. This invention is now described in detail.
The xe2x80x9cwater-insoluble medicinally active substancexe2x80x9d which can be used in the pharmaceutical composition of the instant application includes any and all medicinally active substances that are insoluble in water, such as, for example, tricyclic compounds of the formula (I), represented by FK506 mentioned above, and their pharmaceutically acceptable salts. 
(wherein each of adjacent pairs of R1 and R2, R3 and R4 or R5 and R6 independently
(a) is two adjacent hydrogen atoms, or
(b) may form another bond formed between the carbon atoms to which they are attached,
and further, R2 may be an alkyl group;
R7 is a hydrogen atom, a hydroxy group, a protected hydroxy group or an alkoxy group, or an oxo group together with R1;
each of R8 and R9 is independently a hydrogen atom or a hydroxy group;
R10 is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups or an alkyl group substituted by an oxo group;
X is an oxo group, (a hydrogen atom and a hydroxy group), (a hydrogen atom and a hydrogen atom), or a group represented by the formula xe2x80x94CH2Oxe2x80x94;
Y is an oxo group, (a hydrogen atom and a hydroxy group), (a hydrogen atom and a hydrogen atom), or a group represented by the formula Nxe2x80x94NR11R12 or Nxe2x80x94OR3;
each of R11 and R12 is independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group;
each of R13, R14, R15, R16, R17, R18, R19, R22 and R23 is independently a hydrogen atom or an alkyl group;
each of R20 and R21 is independently an oxo group or (R20a and a hydrogen atom) or (R21a and a hydrogen atom) in which each of R20a and R21a is independently a hydroxy group, an alkoxy group or a group represented by the formula xe2x80x94OCH2OCH2CH2OCH3, or R21a is a protected hydroxy group, or R20a and R21a may together represent an oxygen atom in an epoxide ring;
n is an integer of 1 or 2; and
in addition to the above definitions, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkyl substituted by one or more hydroxy groups, an alkoxy, a benzyl and a group of the formula xe2x80x94CH2Se(C6H5)).
The compound (I) and its pharmaceutically acceptable salt are known as immunosuppressants (Japanese Tokkyo Kokai Koho S61-148181, EP0323042), and FK506, inparticular, has already been put to use in the therapy and prophylaxis of rejection reactions by transplantation of organs such as the heart, liver, kidney, bone marrow, skin, cornea, lung, pancreas, small intestine, muscle, nerve, limb, etc. and of various autoimmune diseases.
The above-mentioned compound (I) and its pharmaceutically acceptable salt can be provided by the same methods as disclosed in the two patent gazettes mentioned above. Particularly the tricyclic compounds produced by cultivation of Streptomyces tsukubaensis No. 9993 (FERM-BP 927) or Streptomyces hygroscopicus subsp. yakushimaensis No. 7238 (FERM-BP 928) have been given the identification numbers FR-900506, FR-900520, FR-900523, and FR-900525 (Japanese Tokkyo Kokai Koho S61-148181).
First, the definitions used in the above general formula (I) and the specific and preferred examples thereof are now explained and set forth in detail.
The term xe2x80x9clowerxe2x80x9d means, unless otherwise indicated, a group having 1 to 6 carbon atoms.
Preferable examples of the xe2x80x9calkyl groupsxe2x80x9d include a straight or branched chain aliphatic hydrocarbon residue, for example, a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl and hexyl.
Preferable examples of the xe2x80x9calkenyl groupsxe2x80x9d include a straight or branched chain aliphatic hydrocarbon residue having one double-bond, for example, a lower alkenyl group such as vinyl, propenyl (e.g., allyl group), butenyl, methylpropenyl, pentenyl and hexenyl.
Preferable examples of the xe2x80x9caryl groupsxe2x80x9d include phenyl, tolyl, xylyl, cumenyl, mesityl and naphthyl.
Preferable protective groups in the xe2x80x9cprotected hydroxy groupsxe2x80x9d are 1- (lower alkylthio) (lower) alkyl group such as a lower alkylthiomethyl group (e.g., methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), more preferably C1-C4 alkylthiomethyl group, most preferably methylthiomethyl group;
trisubstituted silyl group such as a tri(lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl, tri-tert-butylsilyl, etc.) or lower alkyldiarylsilyl (e.g., methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenyl-silyl, etc.), more preferably tri (C1-C4) alkylsilyl group and C1-C4 alkyldiphenylsilyl group, most preferably tert-butyldimethylsilyl group and tert-butyldiphenylsilyl group; and an acyl group such as an aliphatic, aromatic acyl group or an aliphatic acyl group substituted by an aromatic group, which are derived from a carboxylic acid, sulfonic acid or carbamic acid.
Examples of the aliphatic acyl groups include a lower alkanoyl group optionally having one or more suitable substituents such as carboxy, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, arboxyhexanoyl, etc.; a cyclo(lower)alkoxy(lower)alkanoyl group optionally having one or more suitable substituents such as lower alkyl, e.g., cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl, menthyloxyhexanoyl, etc.; a camphorsulfonyl group; or a lower alkylcarbamoyl group having one or more suitable substituents such as carboxy or protected carboxy, for example, carboxy(lower)alkylcarbamoyl group (e.g., carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl, etc.), tri(lower)alkylsilyl(lower)alkoxycarbonyl(lower)alkylcarbamoyl group (e.g., trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsilylethoxycarbonylpropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl, etc.) and so on.
Examples of the aromatic acyl groups include an aroyl group optionally having one or more suitable substituents such as nitro, e.g., benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl, etc.; and an arenesulfonyl group optionally having one or more suitable substituents such as halogen, e.g., benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.
Examples of the aliphatic acyl groups substituted by an aromatic group include ar(lower)alkanoyl group optionally having one or more suitable substituents such as lower alkoxy or trihalo(lower)alkyl, e.g., phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl-2-propoxy-2-phenylacetyl, etc.
More preferable acyl groups among the aforesaid acyl groups are C1-C4 alkanoyl group optionally having carboxy, cyclo(C5-C6)alkoxy(C1-C4)alkanoyl group having two (C1-C4) alkyls at the cycloalkyl moiety, camphorsulfonyl group, carboxy(C1-C4) alkylcarbamoyl group, tri(C1-C4) alkylsilyl (C1-C4)alkoxycarbonyl(C1-C4)alkylcarbamoyl group, benzoyl group optionally having one or two nitro groups, benzenesulfonyl group having halogen, or phenyl(C1-C4)alkanoyl group having C1-C4alkoxy and trihalo(C1-C4)alkyl group. Among these, the most preferable ones are acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethyl-2-methoxy-2-phenylacetyl.
Preferable examples of the xe2x80x9c5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ringxe2x80x9d include a pyrrolyl group and a tetrahydrofuryl group.
The pharmaceutically acceptable salt of the compound (I) includes conventional non-toxic and pharmaceutically acceptable salt such as the salt with inorganic or organic bases, specifically, an alkali metal salt such as sodium salt and potassium salt, an alkali earth metal salt such as calcium salt and magnesium salt, an ammonium salt and an amine salt such as triethylamine salt and N-benzyl-N-methylamine salt.
With respect to the compound (I), it is to be understood that there may be conformers and one or more stereoisomers such as optical and geometrical isomers due to asymmetric carbon atom(s) and double bond(s), and such conformers and isomers are also included within the scope of the present invention.
The compound of the formula (I) and its salt can be in the form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate.
The preferred examples of the tricyclic compound (I) is the one, wherein each of adjacent pairs of R3 and R4 or R5 and R6 independently form another bond formed between the carbon atoms to which they are attached;
each of R8 and R23 is independently a hydrogen atom;
R9 is a hydroxy group;
R10 is a methyl group, an ethyl group, a propyl group or an allyl group;
X is (a hydrogen atom and a hydrogen atom) or an oxo group;
Y is an oxo group;
each of R14, R15, R16, R17, R18, R19, and R22 is a methyl group;
each of R20 and R21 is independently (R20a and a hydrogen atom) or (R21a and a hydrogen atom) in which each of R20a and R21a is a hydroxy group or an alkoxy group, or R21a is a protected hydroxy group; and
n is an integer of 1 or 2. FK506 is the most preferable compound belonging to the tricyclic compound (I). Other preferable compounds are listed hereinbelow.
1,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,17,19,21,27-pentamethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone,
12-[2-(4-acetoxy-3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone,
17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-12-[2-[4-(3,5-dinitrobenzoyloxy)-3-methoxycyclo-hexyl]-1-methylvinyl]-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone,
17-allyl-12-[2-[4-[(xe2x88x92)-2-trifluoromethyl-2-methoxy-2-phenylacetoxy]-3-methoxycyclohexyl]-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone.
17-ethyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclo-hexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (FR900520), and
17-ethyl-1,14,20-trihydroxy-12-[2-(3,4-dihydroxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone.
As other examples of the water-insoluble medicinally active substance which can be used in the present invention, there can be mentioned the following urea derivative (II) and its pharmacologically acceptable salt. 
[wherein R24 represents aryl optionally substituted by halogen, nitro, amino, lower alkylamino, lower alkoxy or acylamino,
R25 represents hydrogen; alkyl; cycloalkyl; or lower alkyl substituted by cyclo(lower) alkyl, cyclo(lower)alkenyl, heterocyclyl, or aryl which may have substituents selected from the class consisting of halogen, hydroxy, and lower alkoxy; R26 represents hydrogen, lower alkyl, or aryl which may be substituted by halogen, nitro, amino or lower alkylamino;
R27 represents hydrogen, halogen, lower alkyl, lower alkoxy, or aryl which may be substituted by halogen;
R28 represents hydrogen, halogen, lower alkyl or aryl,
A represents a single bond or lower alkylene,
Z represents O, S, or NH]
The various definitions used in the general formula (II) representing the above urea derivative and the preferred examples are now described in detail.
The term xe2x80x9clowerxe2x80x9d is used here in reference to any group containing 1 to 6 carbon atoms unless otherwise specified.
The term xe2x80x9clowerxe2x80x9d as used for said xe2x80x9ccyclo(lower)alkylxe2x80x9d means a carbon number of 3 to 6. The term xe2x80x9clowerxe2x80x9d as used for said xe2x80x9ccyclo(lower)alkenylxe2x80x9d means a carbon number of 3 to 6.
The term xe2x80x9calkylxe2x80x9d is used here to encompass both lower alkyl and higher alkyl groups.
The term xe2x80x9ccycloalkylxe2x80x9d may mean both cyclo(lower)alkyl and cyclo(higher)alkyl.
The preferred xe2x80x9clower alkylxe2x80x9d and xe2x80x9clower alkylxe2x80x9d moiety of said xe2x80x9clower alkylaminoxe2x80x9d or xe2x80x9car (lower) alkylxe2x80x9d includes straight-chain or branched alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, and hexyl. Particularly preferred lower alkyl groups are methyl, ethyl, propyl, isopropyl, pentyl, and isopentyl.
The preferred xe2x80x9ccyclo(lower)alkylxe2x80x9d includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The preferred xe2x80x9ccyclo(lower)alkenylxe2x80x9d includes cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
The term xe2x80x9chigherxe2x80x9d as used herein means a carbon number of 7 to 20 unless otherwise indicated. The preferred xe2x80x9chigher alkylxe2x80x9d includes such straight-chain and branched alkyl groups as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, methylheptyl, methyloctyl, methylnonyl, methyldecyl, ethylheptyl, ethyloctyl, ethylnonyl, and ethyldecyl. The more preferred are alkyl groups of 7 to 10 carbon atoms and the most preferred is heptyl or nonyl.
The preferred xe2x80x9ccyclo(higher)alkylxe2x80x9d includes cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, cycloheptadecyl, cyclooctadecyl, cyclononadecyl, and cycloeicosyl. Particularly preferred are those containing 7 to 10 carbon atoms. The most preferred is cycloheptyl.
The preferred xe2x80x9clower alkoxyxe2x80x9d includes straight-chain or branched alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc., with methoxy being the most useful.
The preferred xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine, bromine, and iodine, with fluorine or chlorine being particularly useful.
The preferred xe2x80x9carylxe2x80x9d includes phenyl, naphthyl, and phenyl substituted by lower alkyl (e.g. tolyl, xylyl, mesityl, cumenyl, diisopropylphenyl, etc.). The more preferred is phenyl or phenyl substituted by lower alkyl.
The preferred xe2x80x9clower alkylaminoxe2x80x9d includes mono- or di- (lower alkyl) amino groups such as methylamino, ethylamino, dimethylamino, diethylamino, etc., with dimethylamino being particularly useful. The preferred xe2x80x9car(lower)alkylxe2x80x9d includes but is not limited to phenyl (lower) alkyl (e.g. benzyl, phenethyl, phenylpropyl, etc.), benzhydryl, trityl, tolylmethyl, xylylmethyl, mesitylmethyl, and cumenylmethyl, with phenyl(lower)alkyl being particularly preferred. The most useful is benzyl.
The preferred xe2x80x9clower alkylenexe2x80x9d includes straight-chain or branched alkylene groups such as, for example, methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, and ethylethylene. The aryl for R24, R26, and R27 may be substituted by 1xcx9c5 of the above-mentioned substituent groups. The preferred number of substituents is 1, 2, or 3.
The aryl as a substituent on the lower alkyl for R25 may be substituted by 1xcx9c5 of said substituent groups, and the preferred number of substituents is 1, 2, or 3.
The preferred xe2x80x9caryl substituted by halogenxe2x80x9d includes chlorophenyl, dichlorophenyl, difluorophenyl, trichlorophenyl, and trifluorophenyl.
The preferred xe2x80x9cheterocyclic group (heterocyclyl)xe2x80x9d includes monocyclic or polycyclic hetero-ring residues, whether saturated or unsaturated, each containing at least one hetero-atom selected from among nitrogen, oxygen, and sulfur.
The preferred xe2x80x9cheterocyclic groupxe2x80x9d as defined above includes 3- through 8-membered, preferably 5- or 6-membered, unsaturated monocyclic hetero systems each containing 1xcx9c4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl-N-oxide, dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazinyl, tetrazolyl, etc.; 3- through 8-membered, preferably 5- or 6-membered, saturated monocyclic hetero systems each containing 1xcx9c4 nitrogen atoms such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc., unsaturated fused heterocyclic residues each containing 1xcx9c5 nitrogen atoms such as indolyl, isoindolyl, indolidinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;
3- through 8-membered unsaturated monocyclic hetero systems each containing 1 or 2 oxygen atoms and 1xcx9c3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl, etc.; 3- through 8-membered saturated monocyclic hetero systems each containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholino, sydnonyl, etc.; unsaturated fused heterocyclic groups each containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl, benzoxadiazolyl, etc.;
3- through 8-membered unsaturated monocyclic hetero systems each containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl, etc.; 3- through 8-membered unsaturated monocyclic hetero systems each containing 1 or 2 sulfur atoms, such as thienyl; unsaturated fused heterocyclic groups each containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl, benzothiadiazolyl, etc.; 3- through 8-membered unsaturated monocyclic hetero systems each containing 1 oxygen atom, such as furyl; unsaturated fused heterocyclic groups each containing 1 or 2 sulfur atoms, such as benzothienyl; and unsaturated fused heterocyclic groups each containing 1 or 2 oxygen atoms, such as benzofuranyl.
Preferably, the heterocyclic group is pyridyl or furyl.
The preferred acyl moiety of said xe2x80x9cacylaminoxe2x80x9d includes carboxy; esterified carboxy; carbamoyl optionally having substituent groups selected from the class consisting of lower alkyl, cyclo(lower)alkyl, aryl, and hydroxy; lower alkanoyl; heterocyclylcarbonyl; and lower alkylsulfonyl; among others.
The esterified carboxy includes but is not limited to substituted or unsubstituted lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), substituted or unsubstituted aryloxycarbonyl ((e.g. phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.), and substituted or unsubstituted ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxy-carbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.).
The xe2x80x9clower alkanoylxe2x80x9d includes but is not limited to formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl. Particularly preferred is acetyl.
The heterocyclic moiety of said xe2x80x9cheterocyclylcarbonylxe2x80x9d includes the same groups as mentioned for said xe2x80x9cheterocyclic groupxe2x80x9d.
The xe2x80x9clower alkylsulfonylxe2x80x9d includes but is not limited to methylsulfonyl, ethylsulfonyl, and propylsulfonyl, with methylsulfonyl being particularly useful.
The preferred xe2x80x9cacylaminoxe2x80x9d includes lower alkanoylamino and lower alkylsulfonylamino. Particularly preferred is acetylamino or methylsulfonylamino.
The preferred pharmacologically acceptable salt of compound (II) includes nontoxic salts of the conventional types, such as inorganic acid addition salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), organic acid addition salts (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), and alkali metal salts (e.g. sodium salt, potassium salt, etc.).
The above-mentioned urea derivative (II) and pharmacologically acceptable salt thereof are already known from inter alia Japanese Tokkyo Kokai Koho H5-140102, as compounds which are useful for prevention and treatment of hypercholesterolemia, hyperlipidemia, and atherosclerosis, and can be produced by the method described therein.
The surfactant which is to be used in accordance with this invention is now described.
The surfactant that can be used includes pharmaceutically acceptable natural or synthetic surfactants. As natural surfactants, a variety of surfactants of the animal origin or of the vegetable origin can be employed. Synthetic surfactants can be used regardless of whether they are cationic, anionic, or nonionic.
To mention preferred examples, the following surfactants can be employed.
Polyoxyethylene alkyl ethers (polyoxyethylene oleyl ethers, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene lauryl ether (Lauromacrogol (Japanese Pharmacopoeia), etc.)
Polyoxyethylene sorbitan fatty acid esters (Tween 20(trademark), Tween 40(trademark), Tween 6(trademark), Tween 65(trademark), Tween 80(trademark), etc.)
Polyoxyethylene glyceryl fatty acid monoesters (polyoxyethylene glyceryl monostearate etc.)
Polyoxyethylene propylene glycol fatty acid monoesters (polyoxyethylene propylene glycol monostearate, polyoxyethylene propylene glycol monooleate, etc.)
Polyoxyethylene sorbitol fatty acid esters (polyoxyethylene sorbitol tetraoleate, polyoxyethylene sorbitol hexastearate, polyoxyethylene sorbitol monolaurate, polyoxyethylene sorbitol beeswax, etc.)
Polyoxyethylene derivatives of natural oils and waxes (polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil (HCO-40, HCO-60, Cremophor RH40, Cremophor RH60, etc.; all trademarks), polyoxyethylene lanolin, etc.)
Polyethylene glycol fatty acid esters (polyethylene glycol monooleate, polyethylene glycol monostearate (polyoxyl stearate 40 (Japanese Pharmacopoeia), etc.), polyethylene glycol monolaurate, etc.)
Propylene glycol fatty acid mono- or diesters (propylene glycol monocaprylate (Sefsol-218(trademark) etc.), propylene glycol dicaprylate (Sefsol-228(trademark) etc.), propylene glycol monocaprate, propylene glycol dicaprate (Sefsol-220(trademark) etc.), propylene glycol monolaurate, propylene glycol monoisooctanoate (Sefsol-2126(trademark) etc.), propylene glycol diisooctanoate (Sefsol-2226(trademark) etc.), Miglyol 840(trademark), etc.)
Sorbitan fatty acid esters (sorbitan monooleate (Span 80(trademark) etc.), sorbitan monostearate (Span 60(trademark) etc.), sorbitan monopalmitate (Span 40(trademark) etc.), sorbitan monolaurate (Span 20(trademark) etc.), sorbitan monocaprylate (Sefsol-418(trademark) etc.), etc.)
Sucrose fatty acid esters (DK-SS, DK-F160, DK-F140, DK-F110, all trademarks of Daiichi Kogyo Seiyaku, etc.)
Polyoxyethylene-polyoxypropylene copolymer and block copolymer surfactants (Pluronic F87(trademark), Pluronic F127(trademark), Pluronic F68(trademark), Pluronic L44(trademark), Pluronic P123(trademark), Pluronic P85(trademark), Poloxamer 188(trademark), Poloxamer 235(trademark), Poloxamer 403(trademark), Poloxamer 407(trademark), etc.)
Sulfuric acid alkyl ester salts (sodium lauryl sulfate etc.)
Phospholipids (purified egg yolk lecithin, purified soybean lecithin, etc.)
Bile acid salts (sodium taurocholate, sodium glycocholate, etc.),
Fatty acids (oleic acid, linoleic acid, etc.)
Monohydric alcohol fatty acid esters (isopropyl myristate, butyl myristate, isocetyl myristate, octyldodecyl myristate, isopropyl palmitate, isostearyl palmitate, isopropyl isostearate, isocetyl isostearate, butyl stearate, isocetyl stearate, cetyl isooctanoate, ethyl linoleate, isopropyl linoleate, hexyl laurate, ethyl oleate, decyl oleate, oleyl oleate, octyldodecyl myristate, hexyldecyl dimethyloctanoate, octyldodecyl neodecanoate, etc.)
Ethylene glycol fatty acid esters (ethylene glycol monocaprylate (Sefsol-118(trademark) etc.), ethylene glycol dicaprylate (Sefsol-128(trademark) etc.), ethylene glycol monoisooctanoate (Sefsol-1126(trademark) etc.), ethylene glycol diisooctanoate (Sefsol-1226(trademark) etc.), etc.
Other polyhydric alcohol fatty acid esters [tetraglycerin monocaprylate (Sefsol-618(trademark) etc.), tetraglycerin hexacaprylate (Sefsol-668(trademark) etc.), etc.]
Dibasic acid diesters (diisopropyl adipate, diisobutyl adipate, diethyl sebacate, diisopropyl sebacate, diethyl phthalate, etc.)
Alcohols (oleyl alcohol, cetanol, stearyl alcohol, etc.)
Others (squalane, squalene, etc.).
In accordance with the present invention, the above-mentioned surfactants can be used each alone or in combination.
More preferable surfactants are polyoxyethylene hydrogenated castor oil, sucrose fatty acid esters, propylene glycol fatty acid mono- or di-esters, polyoxyethylene sorbitan fatty acid esters, and so on, and the most preferable one is the combinaiton of polyoxyethylene hydrogenated castor oil and propylene glycol fatty acid mono- or di-esters.
The term xe2x80x9csolid dispersionxe2x80x9d used in the present invention is the well known one, and which is a solid one wherein a medicinally active substance is being dispersed as an amorphous form in an inert carrier or matrix thereof as explained in, for example, J. Pharm. Sci. 60(9) p1281- (1971), incorporated by reference.
The solid carrier for use in the present invention includes any and all pharmaceutically acceptable solid carriers which can form a solid dispersion with a water-insoluble medicinally active substance, but is preferably selected from among the following substances.
Polymers [polyvinylpyrrolidone, polyvinylpolypyrrolidone, cellulose polymers (hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose, ethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, cystalline cellulose, etc.), pectin, cyclodextrins, galactomannan, polyethylene glycol with a mean molecular weight of not less than 4000, gelatin, etc.]
Saccharides (dextrose, sucrose, galactose, sorbitol, maltose, xylitol, mannitol, lactose, etc.)
Acids (citric acid, succinic acid, etc.)
Others (light anhydrous silicic acid, pentaerythritol, pentaerythrytyl tetracetate, urea, hydroxyalkylxanthines, urethane, etc.)
Incidentally, those carriers can be used each alone or in combination. Preferable solid carriers are water-soluble ones, such as water-soluble polymers (e.g., cellulose polymers, polyvinylpyrrolidone, and so on); saccharides; light anhydrous silicic acid; and so on. And most preferable one is hydroxypropylmethylcellulose, polyvinylpyrrolidone, lactose, light anhydrous silicic acid, or their combination.
Optionally in addition to the above components, the conventional excipients (e.g. starch, etc), disintegrators (e.g. croscarmellose sodium, carboxymethylcellulose calcium, low substituted hydroxypropylcellulose, starch glycolate sodium, microcrystalline cellulose, crospovidone, etc.), coloring agents, sweeteners, flavors, diluents, antioxidant (e.g., vitamin E, etc) and lubricants (e.g., synthetic aluminum silicate, magnesium stearate, calcium stearate, talc, etc.) can be incorporated.
Meanwhile, the technology for manufacturing the pharmaceutical composition of the invention is now described.
The water-insoluble medicinally active substance and the surfactant are thoroughly dissolved in organic solvent(s) (e.g. ethanol) and a suitable amount of the solid carrier is added thereto. Then the mixture is kneaded well. After removing the organic solvent therefrom, the resultant residue is dried and pulverized to provide a solid pharmaceutical composition of the invention. In the kneading procedure referred to above, excipient(s) and disintegrator(s), such as low substituted hydroxypropylcellulose (L-HPC-21), may be further added where necessary.
While the effective dosage of said water-insoluble medicinally active substance depends on the type of the said substance, the patient""s age, type of disease, severity of illness, and other factors, a daily dose of the active substance is about 0.01xcx9c1000 mg, preferably 0.05xcx9c500 mg, and more preferably, 0.1xcx9c100 mg for therapeutic purposes. The average unit dose may be generally about 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg, or 500 mg.
The proportions of the respective components of the pharmaceutical composition of the present invention are preferably selected according to their species but the following formulas may be mentioned as preferred examples.
The recommended proportion of said water-insoluble medicinally active substance relative to the total composition is 0.01xcx9c20% and preferably 0.1xcx9c10%.
The preferable weight ratio of the water-insoluble medicinally active substance, the surfactant and the solid carrier is 1:0.1xcx9c100:1xcx9c300, and more preferable one is 1:1xcx9c50:5xcx9c150. The most preferable one is 1:4xcx9c40:10xcx9c100.
Further, it is more preferable to add disintegrators as a component(s). In that case, the ratio of the said disintegrators among the total weight is 1-60%, and the more preferable one is 2-30%.
The following examples are intended to describe the invention in further detail and should not be construed as limiting the scope of the invention.
Using bulk powders of N-benzyl-N-[3-(4-chlorophenyl)-5-methylbenzofuran-2-ylmethyl]-Nxe2x80x2-(2,4,6-trifluorophenyl)urea (hereinafter referred to briefly as compound M) as prepared in the same manner as Example 6 (2) of Japanese Tokkyo Kokai Koho H5-140102, the following composition was provided.
Compound M bulk powders (100 mg), propylene glycol monocaprylate (0. 6 g) and sucrose fatty acid ester (1 g) were added into ethanol (25 ml) and dissolved thoroughly. To this solution, was added hydroxypropylmethylcellulose (3.3 g) and then it was allowed to swell sufficiently. After that, it was kneaded and added low substituted hydroxypropylcellulose (5 g), and further kneaded. The resultant mixture was transferred to a stainless steel tray and was dried in vacuo for 24 hours, and then pulverized in amortar. The pulverized powder was sieved through a 32-mesh screen and was dried in vacuo for 24 hours again to provide Composition A.
The following compositions of Examples 2 and 3 were respectively prepared by using the same procedure as described in Example 1.
A dissolution test was performed in conformity with Method 2 (Paddle method) of the Japanese Pharmacopoeia(JP). As the test solution, 900 ml of water was used. The paddle speed was set to 50 rpm. The Composition A prepared in Example 1 was added to the test solution and after 5, 15, 30, 60, 90 and 120 minutes, 0.3 ml aliquots of the test solution were taken as samples. Each sample was centrifuged at 10000 rpm for 3 minutes and 0.1 ml of the supernatant was taken into a plastic tube containing 0.4 ml of methanol. After blending, the mixture was filtered through a 0.5 xcexcm filter and analyzed by high-performance liquid chromatography. Using the Composition A of Example 1, the above procedure was repeated for a total of 3 times (n=3).
The results are presented in FIG. 1.
As a control composition, a solid dispersion (composed of bulk powders of compound M (10 mg) which were prepared in the same manner as Example 4 of Japanese Tokkyo Kokai Koho S62-277321, hydroxypropylmethyl-cellulose (40 mg) and low substituted hydroxypropylcellulose (50 mg)) was used.
It is clear from the plots in FIG. 1 that the composition of the present invention has very satisfactory dissolution property.
(1) Test Method
The following test composition and control composition were respectively administered orally to male beagle dogs (3xcx9c6 per group) for comparison of oral absorbability. The body weights of dogs were about 12 kg, and the animals were deprived of food for 24 hours before dosing (dosage as FK506=1 mg/dog). However, drinking water was available throughout the experiment. The dosage of the composition was carried out.around 9:30 a.m. and 40 ml of water was given at the same time. At predetermined intervals after dosing, 1 ml of blood was drawn from the forearm vein using a sterilized syringe into a heparin-containing plastic tube and stored at about xe2x88x9280xc2x0 C. until determination of drug concentration. The whole blood concentration of the active substance was determined by the FK506-specific enzyme immunoassay (EIA) which was well known from Japanese Tokkyo Kokai Koho H1-92659. The maximum blood concentration (Cmax) was the maximum value of whole blood drug concentrations at respective time-points of determination and the area under the blood concentration-time curve (AUC) was calculated by the trapezoid method.
In addition, as an indicator of variation in oral absorbability, the CV value (standard deviation/mean) was also calculated. The results are presented in Table 1.
(2) Test Compositions
Composition According to Example 3 (19)
Control Composition
A composition (1 mg capsule) according to the following formula as prepared in the same manner as Examples 1 and 2 of WO 91/19495 (by adding (e) and (f) to a solid dispersion of (a)xcx9c(d) and encapsulating the mixture)
It is clear from Table 1 that the pharmaceutical composition of the present invention has an excellent oral absorbability with high absorption and less variation in said absorption.
The patents, patent applications and publications cited herein are incorporated by reference.
The pharmaceutical composition of the present invention is a solid dispersion having various favorable characteristics such as good stability, good workability, high dissolution property and/or an excellent oral absorbability with high absorption and/or less variation in said absorption. The present invention has enabled the provision of oral dosage forms for compounds, for which any attempt in the past to develop oral products has to be abandoned because of their poor solubility in water or poor absorbability after oral administration or whose potential utility as medicines have not sufficiently been performed heretofore.
The composition of the invention can be administered by various routes, for example externally, parenterally, or by administering into the eye or the nostrils. For oral administration, the composition is ingested directly as capsules, tablets, granules, fine granules, or some other dosage form or it is beforehand dispersed in water, a juice, etc. and ingested in a liquid form. For external application, the composition can be dispersed in water or the like medium and applied in the form of a lotion. For use as an injection, the composition is dispersed in water, saline, or the like and administered. For use as nose-drops, the composition is dispersed in water beforehand and administered into the nostrils. For use as an ophthalmic solution, the composition is dispersed in water, an isotonic buffer solution, or the like and instilled in the eye.
Furthermore, by judicious selection of species of respective components, particularly solid carriers, the dissolution rate and/or release rate can be controlled to provide sustained-release compositions.
When said tricyclic compound (I) is used as the water-insoluble medicinally active substance, the pharmaceutical composition of the present invention is useful for the treatment and prevention of the following diseases and conditions because of the pharmacologic activities possessed by said tricyclic compound (I).
Rejection reactions by transplantation of organs or tissues such as the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, intervertebral disc, trachea, myoblast, cartilage, etc.;
graft-versus-host reactions following bone marrow transplantation;
autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto""s thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, etc.;
and infections caused by pathogenic microorganisms (e.g. Aspergillus fumigatus, Fusarium oxysporum, Trichophyton asteroides, etc.).
Furthermore, pharmaceutical preparations of said tricyclic compound (I) are useful for the therapy and prophylaxis of the following diseases.
Inflammatory or hyperproliferative skin diseases or cutaneous manifestations of immunologically-mediated diseases (e.g. psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, erythema, dermal eosinophilia, lupus erythematosus, acne, and alopecia areata);
autoimmune diseases of the eye (e.g. keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet""s disease, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren""s ulcer, scleritis, Graves"" ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca(dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, etc.);
reversible obstructive airways diseases [asthma (e.g. bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma), particularly chronic or inveterate asthma (e.g. late asthma and airway hyper-responsiveness) bronchitis, etc.];
mucosal or vascular inflammations (e.g. gastric ulcer, ischemic or thrombotic vascular injury, ischemic bowel diseases, enteritis, necrotizing enterocolitis, intestinal damages associated with thermal burns, leukotriene B4-mediated diseases);
intestinal inflammations/allergies (e.g. coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn""s disease and ulcerative colitis);
food-related allergic diseases with symptomatic manifestation remote from the gastrointestinal tract (e.g. migrain, rhinitis and eczema);
renal diseases (e.g. intestitial nephritis, Goodpasture""s syndrome, hemolytic uremic syndrome, and diabetic nephropathy);
nervous diseases (e.g. multiple myositis, Guillain-Barre syndrome, Meniere""s disease, multiple neuritis, solitary neuritis, cerebral infarction, Alzheimer""s diseases Parkinson""s diseases amyotrophic lateral sclerosis (ALS) and radiculopathy);
cerebral ischemic disease (e.g., head injury, hemorrhage in brain(e.g., subarachnoid hemorrhage, intracerebral hemorrhage), cerebral thrombosis, cerebral embolism, cardiac arrest, stroke, transient ischemic attack (TIA), hypertensive encephalopathy);
endocrine diseases (e.g. hyperthyroidism, and Basedow""s disease);
hematic diseases (e.g. pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, and anerythroplasia);
bone diseases (e.g. osteoporosis);
respiratory diseases (e.g. sarcoidosis, pulmonary fibrosis, and idiopathic interstitial pneumonia);
skin diseases (e.g. dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photosensitivity, and cutaneous T-cell lymphoma);
circulatory diseases (e.g. arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, and myocardosis); collagen diseases (e.g. scleroderma, Wegener""s granuloma, and Sjogren""s syndrome);
adiposis;
eosinophilic fasciitis;
periodontal diseases (e.g. damage to gingiva, periodontium, alveolar bone or substantia ossea dentis);
nephrotic syndrome (e.g. glomerulonephritis);
male pattern alopecia, alopecia senile;
muscular dystrophy;
pyoderma and Sezary syndrome;
chromosome abnormality-associated diseases (e.g. Down""s syndrome);
Addison""s disease;
active oxygen-mediated diseases [e.g. organ injury (e.g. ischemic circulation disorders of organs (e.g. heart, liver, kidney, digestive tract, etc.) associated with preservation, transplantation, or ischemic diseases (e.g. thrombosis, cardial infarction, etc.)):
intestinal diseases (e.g. endotoxin shock, pseudomembranous colitis, and drug- or radiation-induced colitis):
renal diseases (e.g. ischemic acute renal insufficiency, chronic renal failure):
pulmonary diseases (e.g. toxicosis caused by pulmonary oxygen or drugs (e.g. paracort, bleomycin, etc.), lung cancer, and pulmonary emphysema):
ocular diseases (e.g. cataracta, iron-storage disease (siderosis bulbi), retinitis, pigmentosa, senile plaques, vitreous scarring, corneal alkali burn):
dermatitis (e.g. erythema multiforme, linear immunoglobulin A bullous dermatitis, cement dermatitis):
and other diseases (e.g. gingivitis, periodontitis, sepsis, pancreatitis, and diseases caused by environmental pollution (e.g. air pollution), aging, carcinogen, metastasis of carcinoma, and hypobaropathy)];
diseases caused by histamine release or leukotriene C4 release;
restenosis of coronary artery following angioplasty and prevention of postsurgical adhesions;
Autoimmune diseases and inflammatory conditions (e.g., primary mucosal edema, autoimmune atrophic gastritis, premature menopause, male sterility, juvenile diabetes mellitus, pemphigus vulgaris, pemphigoid, sympathetic ophthalmitis, lens-induced uveitis, idiopathic leukopenia, active chronic hepatitis, idiopathic cirrhosis, discoid lupus erythematosus, autoimmune orchitis, arthritis (e.g. arthritis deformans), orpolychondritis);
Human Immunodeficiency Virus (HIV) infections AIDS;
allergic conjunctivitis;
hypertrophic cicatrix and keloid due to trauma, burn, or surgery.
In addition, the tricyclic compound (I) has liver regenerating activity and/or activities of stimulating hypertrophy and hyperplasia of hepatocytes.
Therefore, the pharmaceutical composition of the present invention is useful for the therapy and prophylaxis of liver diseases [e.g. immunogenicdiseases (e.g. chronicautoimmuneliver diseases such as autoimmune hepatic diseases, primary biliary cirrhosis or sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis, shock, or anoxia), hepatitis B, non-A non-B hepatitis, hepatocirrhosis, and hepatic failure (e.g. fulminant hepatitis, late-onset hepatitis and xe2x80x9cacute-on-chronicxe2x80x9d liver failure (acute liver failure on chronic liver diseases))].
And further, the present composition is useful for preventing or treating various diseases because of its useful pharmacological activity such as augmenting activity of chemotherapeutic effect, activity of cytomegalovirus infection, anti-inflammatory activity, inhibiting activity against peptidyl-prolyl isomerase or rotamase, antimalarial activity, antitumor activity, and so on.